Project Abstract Rapid disease progression and chemotherapy resistant disease are frequently observed among the most common T-cell lymphomas (TCL) and the majority of these patients will ultimately succumb to progressive disease within three years of diagnosis. Only a minority (?10%) of patients will achieve a durable remission with novel agents, as the mechanisms promoting TCL progression and chemotherapy resistance are poorly understood and therapeutic strategies to overcome them are not defined. We have recently shown that the T- cell transcription factor GATA-3 identifies a molecularly, genetically, and clinically distinct subset of TCL that are highly resistant to chemotherapy. We have also demonstrated that Notch activation is prevalent in the TCL, and Notch blockade inhibits both TCL proliferation and GATA-3 expression, a Notch target gene, in preliminary studies. Genetic and pharmacologic loss-of-function (and gain-of-function) strategies were performed in genetically diverse TCL cells and subsequently demonstrated that GATA-3 directly confers resistance to chemotherapy in a cell-autonomous fashion. In addition, lymphoma-associated macrophages (LAM) within the tumor microenvironment (TME) promote chemotherapy resistance, and GATA-3 dependent cytokines regulate their functional polarization, highlighting an additional non-cell-autonomous mechanism for GATA-3-dependent chemotherapy resistance. Thus, there is a critical need to identify factors regulating GATA-3 expression and function in these aggressive TCL. In the absence of such knowledge, the development of therapeutic strategies that impair GATA-3-dependent transcriptional regulation and improve outcomes among these TCL will remain elusive. Our long-term goals are to understand the fundamental mechanisms that drive TCL pathogenesis and promote their resistance to currently available therapies. In doing so, we hope to develop rationally designed therapeutic strategies that will overcome the challenge of chemotherapy resistance and improve outcomes for patients afflicted with these TCL. Our overall objectives in this application are to evaluate the role of Notch signaling in T-cell lymphomagenesis and to identify the requirements for optimal GATA-3 DNA binding and transcriptional regulation. These will be achieved by addressing our central hypothesis that Notch and GATA-3 promote TCL progression and resistance to chemotherapy. In addition to being well- grounded in our own preliminary data, our central hypothesis is entirely consistent with our current understanding of the genetic landscape and molecular pathogenesis of the TCL and has significant therapeutic implications.